Bis(dioxopiperazines) are considerable import owing to their antimetastatic properties and their actions ameliorating anthracycline-induced toxicity in animals as reported by Herman et al., 19 Adv. in Pharmacol. and Chemother., 249 (1982).
A morpholinomethyl analogue of the bis(dioxopiperazine) compound known as 1CRF#154 and herein after referred to as Compound I, namely bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-ethane) also known as "bimolane" and hereinafter referred to as Compound II was reported by Ren et al., Kexue Tongbao, 1980:25, 189, to be active, by both the oral and ip routes, against various experimental tumors. Results of the clinical investigations in China indicated that this bimolane, Compound II, may be useful in the treatment of malignant lymphomas, uveitis, sympathetic ophthalmitis and psoriasis (Ren et al., supra). The correlation between the structure of morpholinomethyl-N groups and their behavior in vivo is not well-understood and there is a continuing need for the development of pharmacologically and clinically effective bis(morpholinomethyl) derivatives of bis(dioxopiperazines).
Bimolane (Compound II) is insoluble in water and therefore cannot be employed by intravenous injection. Additionally, it is unclear what is responsible for its antitumor activity since crystals of this material contain Compound I which is the unsubstituted bis(dioxopiperazine( [Camerman et al., Science 225, 1165 (1984)].
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______________________________________ Compound II (Bimolane) ##STR4## Compound V ##STR5## Compound I (ICRF #154) R = H, R' = H Compound III (ICRF #159) R = CH.sub.3, R' = H (dl) Compound IV (ICRF #187) R = CH.sub.3, R' = H (d) ______________________________________
A major limitation to the effective clinical use of daunorubicin or doxorubicin is dose-related cardiomyopathy. Lefrak, E. A.; Pitha, J.; Rosenheim, S.; Gottlieb, J. A., Cancer, (Phil.) 34, 302-314 (1973)][Lefrak, E. A.; Pitha, J.; Rosenheim, S.; O'Brian, R. M.; Burgess, M. A.; Gottlieb, J. A. Cancer Chemother. Repts., 6, 203-208 (1975)]. There is evidence to indicate that bis(dioxopiperazines) can modify daunorubicin or doxorubicin toxicity. In previous studies, pretreatment with 1,2-bis(dioxopiperazinyl)propane (d1) (1CRF#159) (Compound III) caused a significant reduction in high-dose daunorubicin toxicity. [Herman, E. H.; Mhatre, R. M.; Chadwick, D. P. Tox. Appl. Pharmacol., 27, 517 (1974)]. Compound IV (ICRF#187), the more water soluble d isomer of Compound III also reduces the acute toxicity of high doses of daunorubicin. [Herman, E. H.; Ardalan, B.; Bier, C.; Waravdekar, V.; Krop, S. Cancer Treat. Repts., 63, 89 (1979)]. Pretreatment with Compound IV was found to reduce cardiac toxicity in rabbits [Herman, E. H.; Ferrans, V. J.; Jordan, W.; Ardalan, B. Res. Comm. Chem. Path. Pharmacol., 31, 85 (1981)], miniature pigs [Herman, E. H.; Ferrans, V. J. Lab. Invest., 49, 69-77 (1983)], and beagle dogs [Herman, E. H.; Ferrans, V. J. Cancer Res., 41, 3436-3440 (1981)] treated chronically with daunorubucin or doxorubicin. Thus, there is a need for a water soluble bis(dioxopiperazine) which is pure and remains active as an agent which ameliorates anthracycline-induced cardiotoxicity in mammals.